Dataset Information

The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder.

ABSTRACT: The KE family is a large three-generation pedigree in which half the members are affected with a severe speech and language disorder that is transmitted as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 between D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a detailed BAC-/PAC-based sequence map of this interval, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence. We screened the affected chromosome 7 from the KE family with 120 of these STSs (average spacing <100 kb), but we did not detect any evidence of a microdeletion. Novel polymorphic markers were generated from the sequence and were used to further localize critical recombination breakpoints in the KE family. This allowed refinement of the SPCH1 interval to a region between new markers 013A and 330B, containing approximately 6.1 Mb of completed sequence. In addition, we have studied two unrelated patients with a similar speech and language disorder, who have de novo translocations involving 7q31. Fluorescence in situ hybridization analyses with BACs/PACs from the sequence map localized the t(5;7)(q22;q31.2) breakpoint in the first patient (CS) to a single clone within the newly refined SPCH1 interval. This clone contains the CAGH44 gene, which encodes a brain-expressed protein containing a large polyglutamine stretch. However, we found that the t(2;7)(p23;q31.3) breakpoint in the second patient (BRD) resides within a BAC clone mapping >3.7 Mb distal to this, outside the current SPCH1 critical interval. Finally, we investigated the CAGH44 gene in affected individuals of the KE family, but we found no mutations in the currently known coding sequence. These studies represent further steps toward the isolation of the first gene to be implicated in the development of speech and language.

SUBMITTER: Lai CS

PROVIDER: S-EPMC1287211 | biostudies-literature | 2000 Aug

REPOSITORIES: biostudies-literature

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The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder.

Lai C S CS Fisher S E SE Hurst J A JA Levy E R ER Hodgson S S Fox M M Jeremiah S S Povey S S Jamison D C DC Green E D ED Vargha-Khadem F F Monaco A P AP

American journal of human genetics 20000705 2

The KE family is a large three-generation pedigree in which half the members are affected with a severe speech and language disorder that is transmitted as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 between D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a detailed BAC-/PAC-based sequence map of this interval, containing 152 sequence tagged sites (STSs), 20 ...[more]

PMID: 10880297

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Project description:Pathogenic variants of FOXP2 gene were identified first as a monogenic cause of childhood apraxia of speech (CAS), a complex disease that is associated with an impairment of the precision and consistency of movements underlying speech, due to deficits in speech motor planning and programming. FOXP2 variants are heterogenous; single nucleotide variants and small insertions/deletions, intragenic and large-scale deletions, as well as disruptions by structural chromosomal aberrations and uniparental disomy of chromosome 7 are the most common types of mutations. FOXP2-related speech and language disorders can be classified as "FOXP2-only," wherein intragenic mutations result in haploinsufficiency of the FOXP2 gene, or "FOXP2-plus" generated by structural genomic variants (i.e., translocation, microdeletion, etc.) and having more likely developmental and behavioral disturbances adjacent to speech and language impairment. The additional phenotypes are usually related to the disruption/deletion of multiple genes neighboring FOXP2 in the affected chromosomal region. We report the clinical and genetic findings in a family with four affected individuals having expressive speech impairment as the dominant symptom and additional mild dysmorphic features in three. A 7.87 Mb interstitial deletion of the 7q31.1q31.31 region was revealed by whole genome diagnostic microarray analysis in the proband. The FOXP2 gene deletion was confirmed by multiplex ligation-dependent probe amplification (MLPA), and all family members were screened by this targeted method. The FOXP2 deletion was detected in the mother and two siblings of the proband using MLPA. Higher resolution microarray was performed in all the affected individuals to refine the extent and breakpoints of the 7q31 deletion and to exclude other pathogenic copy number variants. To the best of our knowledge, there are only two family-studies reported to date with interstitial 7q31 deletion and showing the core phenotype of FOXP2 haploinsufficiency. Our study may contribute to a better understanding of the behavioral phenotype of FOXP2 disruptions and aid in the identification of such patients. We illustrate the importance of a targeted MLPA analysis suitable for the detection of FOXP2 deletion in selected cases with a specific phenotype of expressive speech disorder. The "phenotype first" and targeted diagnostic strategy can improve the diagnostic yield of speech disorders in the routine clinical practice.

Project description:Autism Spectrum Disorder (ASD) and Childhood Apraxia of Speech (CAS) are developmental disorders with distinct diagnostic criteria and different epidemiology. However, a common genetic background as well as overlapping clinical features between ASD and CAS have been recently reported. To date, brain structural language-related abnormalities have been detected in both the conditions, but no study directly compared young children with ASD, CAS and typical development (TD). In the current work, we aim: (i) to test the hypothesis that ASD and CAS display neurostructural differences in comparison with TD through morphometric Magnetic Resonance Imaging (MRI)-based measures (ASD vs. TD and CAS vs. TD); (ii) to investigate early possible disease-specific brain structural patterns in the two clinical groups (ASD vs. CAS); (iii) to evaluate predictive power of machine-learning (ML) techniques in differentiating the three samples (ASD, CAS, TD). We retrospectively analyzed the T1-weighted brain MRI scans of 68 children (age range: 34-74 months) grouped into three cohorts: (1) 26 children with ASD (mean age ± standard deviation: 56 ± 11 months); (2) 24 children with CAS (57 ± 10 months); (3) 18 children with TD (55 ± 13 months). Furthermore, a ML analysis based on a linear-kernel Support Vector Machine (SVM) was performed. All but one brain structures displayed significant higher volumes in both ASD and CAS children than TD peers. Specifically, ASD alterations involved fronto-temporal regions together with basal ganglia and cerebellum, while CAS alterations are more focused and shifted to frontal regions, suggesting a possible speech-related anomalies distribution. Caudate, superior temporal and hippocampus volumes directly distinguished the two conditions in terms of greater values in ASD compared to CAS. The ML analysis identified significant differences in brain features between ASD and TD children, whereas only some trends in the ML classification capability were detected in CAS as compared to TD peers. Similarly, the MRI structural underpinnings of two clinical groups were not significantly different when evaluated with linear-kernel SVM. Our results may represent the first step towards understanding shared and specific neural substrate in ASD and CAS conditions, which subsequently may contribute to early differential diagnosis and tailoring specific early intervention.

Dataset Information

The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder.

Publications

The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder.

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